双重响应及功能调控多肽自组装体的构建及应用探索

Peptides have excellent biocompatibility, controlled degradation and biological activity. The various functional materials constructed by peptide self-assembly have important application prospects in the fields of drug-controlled release, tissue engineering scaffold and biomineralization. In this project, we intend to study its controllable self-assembly structure in double responsive environment by design several different sequences of peptides which have two response sites that could be triggered by glutathione and alkaline phosphatase, respectively. By regulating the order of response, we could obtain several nanocomposites with different self-assemble morphologies and study the self-assembly rules. Study its biological activity function, to obtain the relationship between peptide configuration and its assembly morphology and biological activity. The effect of various self-assembly structures of peptides on cell takeup and cancer cell inhibition were studied in detail. Prepare fluorescence probe with high specificity and sensitivity and anti-cancer nano drugs with high efficiency and low toxicity. Through this study, we will explore the process regulation of the step-by-step enzyme-responsive peptides, obtain peptide based self-assembled nanomaterials with different morphologies and biological activity. This study provides new ideas and methods for the design of peptide based self-assembly nanomaterials and treatment to specific disease and diagnosis.

多肽具有优良的生物相容性、可控降解性和生物活性，利用多肽自组装技术构建的各种功能性材料在药物控释、组织工程以及生物矿化等领域内有重要的应用前景。本项目拟设计制备不同序列的自组装前体多肽，引入谷胱甘肽催化与碱性磷酸酶催化双重响应位点，研究其在双重调控下的组装行为。通过对催化组装顺序的调控研究多肽的组装规律，得到具有不同形貌的多肽自组装纳米材料，并研究其生物活性功能，获得多肽构型与其组装形貌和生物活性之间的关系规律。重点将研究得到的多种组装结构对细胞摄取、癌细胞抑制等行为和功能的影响。制备具有高特异性和灵敏性的荧光分子探针以及高效低毒的抗癌纳米药物。通过本研究，我们将探索多肽分步（逐级）组装的过程，构建具有不同形貌和生物活性的多肽自组装纳米材料，为多肽类自组装材料的设计与功能调控提供新的思路和方法，为其在疾病特异性诊断和治疗中的应用奠定基础。

在项目资助下，制备了几类具有双重响应能力的功能可调控自组装多肽，并利用癌细胞以及人体免疫细胞检测其癌细胞抑制、免疫诱导等功能，研究了自组装多肽构型与功能之间的关系。同时，还发展了基于自组装多肽的生物活性材料。重要研究成果包括：制备了一种可强烈激活CD8+ T细胞的多肽水凝胶，不仅解决了tuftsin稳定性差的缺点同时增强了免疫激活性能；通过分子设计，利用预组装的方法增强了肽纳米药物的自组装能力和抗肿瘤功效；设计制备了一种可模拟IDF-1功能的多肽，显着降低了体内和体外的炎症反应同时显著抑制动脉粥样硬化。